Mitomycins and the corresponding mitosene analogues are well-known examples of reductive alkylating quionones. The reductive alkylation process involves the formation of an alkylating quinone methide species upon reduction of the quinone and elimination of a leaving group. Since some tumor cells possess a low reduction potential environment, there is a great deal of interest in reductive alkylating quionones as selective antitumor agents. Thus, a wide range of mitomycin and mitosene derivatives have been prepared in an effort to optimize antitumor activity. All of these derivatives possess the indole ring nucleus, but with a variety of substituents.
Our efforts revealed that benzimidazole-based reductive alkylating agents are also capable of forming an alkylating quinone methide species. (See: Skibo, E. B., J. Org. Chem 1986, 51, 522). Altering the indole nucleus of mitosene to benzimidazole (azamitosene) therefore became important to terms of antitumor agent development.
The azamitosenes were found to possess potent in vitro anti-tumor activity against solid tumors such as colon and ovarian cancer. Some azamitosenes were found to provide results which were most favorable when compared to the clinically used drug, mitomycin C.